RESUMEN
BACKGROUND: Vitamin D status in pregnancy may affect offspring neurodevelopment. OBJECTIVE: The objective was to investigate the association between serum 25-hydroxyvitamin D in cord blood and pregnancy and symptoms of attention-deficit hyperactivity disorder in 5-year-old offspring. METHOD: In Odense Child Cohort, Denmark, 944 mother-child pairs had data on pregnancy or cord serum 25-hydroxyvitamin D and parent-rated attention-deficit hyperactivity disorder symptom score by Child Behavior Checklist for ages 1.5-5 years. Adjusted multiple linear regression and two-stage exposure analyses were performed for serum 25-hydroxyvitamin D associations to the attention-deficit hyperactivity disorder symptom score. RESULTS: The mean (standard deviation) serum 25-hydroxyvitamin D in cord blood was 48.0 (21.8) nmol/L; early pregnancy was 65.5 (20.2) nmol/L and late pregnancy was 79.3 (25.7) nmol/L. The median (interquartile range) age of child at examination was 5.2 (5.1-5.4) years and median (interquartile range) attention-deficit hyperactivity disorder symptom score was 2 (0-3) points. In adjusted analyses, serum 25-hydroxyvitamin D of <25 nmol/L and <32 nmol/L in cord blood and <25 nmol/L in early pregnancy was associated with 0.9 [95% confidence interval: 0.4, 1.3], 0.5 [0.1, 0.9] and 2.1 [0.8, 3.4] points higher attention-deficit hyperactivity disorder symptom score vs reference. In the two-stage exposure analysis, attention-deficit hyperactivity disorder symptom score decreased by 0.4 points per 25 nmol/L increase in serum 25-hydroxyvitamin D. Moreover, serum 25-hydroxyvitamin D of <25 nmol/L in early pregnancy and cord was associated with a five-fold and a two-fold risk of attention-deficit hyperactivity disorder symptom score ⩾90th percentile, adjusted odds ratio [95% confidence interval] = 4.9 [1.3, 19.0] and 2.2 [1.2, 3.9]. CONCLUSION: In this cohort, serum 25-hydroxyvitamin D <25 nmol/L in cord blood and early pregnancy were risk factors for higher attention-deficit hyperactivity disorder symptom score in 5-year-old children, suggesting a protective effect of vitamin D on attention-deficit hyperactivity disorder traits at preschool age.
RESUMEN
BACKGROUND: In rare diseases, limited access to services and rare disease experts may force families to act as medical advocates for their child; they can volunteer to support clinician-initiated research or initiate and lead research themselves. Ketotic Hypoglycemia International (KHI) is a new, global organization for families affected by idiopathic ketotic hypoglycemia (IKH) and is run solely by volunteers. Doing research together, families and international experts in a collaborative process such as at KHI, also referred to as patient and public involvement and engagement (PPIE) or extreme citizen science, is often praised for its positive effects on the research and the stakeholders involved. METHODS: We used auto-ethnographic narratives from parents and medical professionals in KHI to report on their experiences with co-produced health research. All co-authors wrote down their experiences in relation to three topics: time invested, work invested and power dynamics. RESULTS: Whilst the parents and health care professionals felt a new hope for (their) children with IKH, they also felt pressure to contribute time or to be flexible in how and when they dedicated time towards the organization. The power dynamics were characterised by a change in the relationship between the parents and medical experts; the parent being taught by the expert shifted to the expert learning from the lived experience of the parent. Both parents and medical experts struggled with maintaining boundaries and safeguarding their mental health. CONCLUSION: Our findings call for the need to secure and prioritize funding for patient organizations, to enable them to create the sustainable architecture required for meaningful PPIE within these organizations. The morals and often deeply personal reasons for engaging with voluntary work in health research, can lead to overstepping of boundaries. As a result of our research, we call for the development of ethics of care guidelines within collaborative health research.
When confronted with a rare disease it is often hard to access information and or medical experts for help. Parents of children affected by idiopathic ketotic hypoglycemia (IKH) have joined in a patient-led organisation to initiate and lead research that could give answers to their medical questions and worries. Medical experts have been invited to join the organisation as members of the Scientific Advisory Board (SAB). When people report on health research conducted in collaboration with patients and or members of the public, they mostly mention positive outcomes. At KHI, some people had left the organisation and we had to deal with some difficult situations; so, we wanted to document and understand these challenges. Nine members of KHI, parents and medical experts, wrote down their stories, using three topics to guide their narrative: time invested, work invested and power dynamics at KHI. Parents and medical experts felt a new hope for (their) children with IKH when working for KHI but they also felt pressured to work at all hours and at the cost of time with their families or their own health. The stories revealed that parents felt less important compared to medical experts, but also that the relationship between parents and experts changed from the parent being taught by the expert, to the expert starting to learn from the lived experience of the parent. To make these collaborations successful we plead for funding for patient-led organisation and ethical guidelines to safeguard volunteers (both medical and lay people).
RESUMEN
Introduction: Well-differentiated pancreatic neuroendocrine tumors (PNETs) can be non-functional or functional, e.g. insulinoma and glucagonoma. The majority of PNETs are sporadic, but PNETs also occur in hereditary syndromes, primarily multiple endocrine neoplasia type 1 (MEN1). The Knudson hypothesis stated a second, somatic hit in MEN1 as the cause of PNETs of MEN1 syndrome. In the recent years, reports on genetic somatic events in both sporadic and hereditary PNETs have emerged, providing a basis for a more detailed molecular understanding of the pathophysiology. In this systematic review and meta-analysis, we made a collation and statistical analysis of aggregated frequent genetic alterations and potential driver events in human grade G1/G2 PNETs. Methods: A systematic search was performed in concordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) reporting guidelines of 2020. A search in Pubmed for published studies using whole exome, whole genome, or targeted gene panel (+400 genes) sequencing of human G1/G2 PNETs was conducted at the 25th of September 2023. Fourteen datasets from published studies were included with data on 221 patients and 225 G1/G2 PNETs, which were divided into sporadic tumors, and hereditary tumors with pre-disposing germline variants, and tumors with unknown germline status. Further, non-functioning and functioning PNETs were distinguished into two groups for pathway evaluation. The collated genetical analyses were conducted using the 'maftools' R-package. Results: Sporadic PNETs accounted 72.0% (162/225), hereditary PNETs 13.3% (30/225), unknown germline status 14.7% (33/225). The most frequently altered gene was MEN1, with somatic variants and copy number variations in overall 42% (95/225); hereditary PNETs (germline variations in MEN1, VHL, CHEK2, BRCA2, PTEN, CDKN1B, and/or MUTYH) 57% (16/30); sporadic PNETs 36% (58/162); unknown germline status 64% (21/33). The MEN1 point mutations/indels were distributed throughout MEN1. Overall, DAXX (16%, 37/225) and ATRX-variants (12%, 27/225) were also abundant with missense mutations clustered in mutational hotspots associated with histone binding, and translocase activity, respectively. DAXX mutations occurred more frequently in PNETs with MEN1 mutations, p<0.05. While functioning PNETs shared few variated genes, non-functioning PNETs had more recurrent variations in genes associated with the Phosphoinositide 3-kinase, Wnt, NOTCH, and Receptor Tyrosine Kinase-Ras signaling onco-pathways. Discussion: The somatic genetic alterations in G1/G2 PNETs are diverse, but with distinct differences between sporadic vs. hereditary, and functional vs. non-functional PNETs. Increased understanding of the genetic alterations may lead to identification of more drivers and driver hotspots in the tumorigenesis in well-differentiated PNETs, potentially giving a basis for the identification of new drug targets. (Funded by Novo Nordisk Foundation, grant number NNF19OC0057915).
Asunto(s)
Tumores Neuroendocrinos , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Tumores Neuroendocrinos/genética , Tumores Neuroendocrinos/patología , Análisis de Secuencia de ADN/métodos , MutaciónRESUMEN
Hyperinsulinemic hypoglycemia (HH) of pancreatic origin includes congenital hyperinsulinism (CHI), insulinoma, insulinomatosis, and adult-onset non-insulinoma persistent hyperinsulinemic hypoglycemia syndrome (NI-PHHS). In this review, we describe the genotype-histotype-phenotype correlations in HH and their therapeutic implications. CHI can occur from birth or later on in life. Histologically, diffuse CHI shows diffuse beta cell hypertrophy with a few giant nuclei per islet of Langerhans, most frequently caused by loss-of-function mutations in ABCC8 or KCNJ11. Focal CHI is histologically characterized by focal adenomatous hyperplasia consisting of confluent hyperplastic islets, caused by a paternal ABCC8/KCNJ11 mutation combined with paternal uniparental disomy of 11p15. CHI in Beckwith-Wiedemann syndrome is caused by mosaic changes in the imprinting region 11p15.4-11p15.5, leading to segmental or diffuse overgrowth of endocrine tissue in the pancreas. Morphological mosaicism of pancreatic islets is characterized by occurence of hyperplastic (type 1) islets in one or a few lobules and small (type 2) islets in the entire pancreas. Other rare genetic causes of CHI show less characteristic or unspecific histology. HH with a predominant adult onset includes insulinomas, which are pancreatic insulin-producing endocrine neoplasms, in some cases with metastatic potential. Insulinomas occur sporadically or as part of multiple endocrine neoplasia type 1 due to MEN1 mutations. MAFA mutations may histologically lead to insulinomatosis with insulin-producing neuroendocrine microadenomas or neuroendocrine neoplasms. NI-PHHS is mainly seen in adults and shows slight histological changes in some patients, which have been defined as major and minor criteria. The genetic cause is unknown in most cases. The diagnosis of HH, as defined by genetic, histological, and phenotypic features, has important implications for patient management and outcome.
Asunto(s)
Hiperinsulinismo Congénito , Humanos , Hiperinsulinismo Congénito/genética , Hiperinsulinismo Congénito/patología , Fenotipo , Mutación , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Hiperinsulinismo/genética , Hiperinsulinismo/patología , Insulinoma/genética , Insulinoma/patología , Hipoglucemia/genética , Genotipo , Estudios de Asociación GenéticaRESUMEN
AIM: We investigated associations between body mass index (BMI) z-scores for children aged 0-2 years and the BMI z-scores, body fat percentage and metabolic risk factors at 3 years of age. METHODS: This was a secondary analysis of the Lifestyle in Pregnancy and Offspring randomised controlled trial, carried out at two university hospitals in Denmark. It comprised 149 mothers with BMI ≥30 kg/m2 who did or did not receive a lifestyle intervention during pregnancy and a reference group of 97 mothers with normal-weight, with follow-up of their 3-year-old offspring. The children in these three groups were pooled for the data analyses, due to similar characteristics between groups. The BMI z-scores were calculated at 5 weeks, 5 months and 1, 2 and 3 years, using Danish reference groups. Their anthropometrics and metabolic outcomes were examined at 3 years of age. RESULTS: BMI z-scores at 5 months to 2 years were associated with BMI z-scores and body fat percentage at 3 years of age and BMI z-scores were not associated with metabolic risk factors at 3 years. CONCLUSION: BMI z-scores from 5 weeks of age were associated with adverse anthropometric outcomes but not with metabolic risk factors at 3 years of age.
Asunto(s)
Madres , Obesidad , Preescolar , Femenino , Humanos , Embarazo , Antropometría , Índice de Masa Corporal , Obesidad/complicaciones , Factores de Riesgo , Recién Nacido , LactanteRESUMEN
INTRODUCTION: Exposure to perfluoroalkyl substances (PFAS) has been associated with lower bone mineral density (BMD) in animal and human studies, but prospective data from children are limited. OBJECTIVES: To determine associations between prenatal and early postnatal PFAS exposure and BMD at age 7 years. METHODS: In the Odense Child Cohort, Denmark, pregnant women were recruited in 2010-2012, and their children were invited for subsequent health examinations. At 12 weeks of gestation the pregnant women delivered a serum sample, and at age 18 months serum was obtained from the child to measure perfluorooctane sulfonic acid(PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA) by LC-MS/MS. At age 7 years DXA scans were performed to measure bone mineral content (BMC) and BMD Z-score. PFAS in pregnancy (n = 881) and/or at age 18 months (n = 668) were regressed against DXA measurements, adjusted for maternal education, child height Z-score, sex (for BMC) and for postnatal exposure, additionally duration of total breastfeeding. We additionally performed structural equation models determining combined effects of pre-and postnatal PFAS exposures. RESULTS: Higher prenatal and early postnatal serum concentrations of all measured PFAS were associated with lower BMC and BMD Z-scores at age 7 years, all estimates were negative although not all significant. For each doubling of 18-month exposure to PFNA or PFOS, BMD Z-scores were lowered by -0.10 (95 % CI -0.19;-0.00) and -0.08 (-0.17;-0.00), respectively after adjustment. Pre- and postnatal PFAS were correlated, but structural equation models suggested that associations with BMD were stronger for 18-month than prenatal PFAS exposure. DISCUSSION: Bone density is established in childhood, and a reduction in BMD during early childhood may have long-term implication for peak bone mass and lifelong bone health. Future studies of the impact of PFAS exposure on fracture incidence will help elucidate the clinical relevance.
Asunto(s)
Ácidos Alcanesulfónicos , Contaminantes Ambientales , Fluorocarburos , Humanos , Niño , Preescolar , Femenino , Embarazo , Lactante , Densidad Ósea , Estudios Prospectivos , Cromatografía Liquida , Contaminantes Ambientales/efectos adversos , Espectrometría de Masas en Tándem , Ácidos Alcanesulfónicos/toxicidad , Fluorocarburos/toxicidadRESUMEN
Maternal dietary factors have been suggested as possible contributing influences for congenital anomalies (CAs). We aimed to assess the association between vitamin D supplementation or vitamin D status (s-25OHD) during pregnancy and CAs in the offspring. A comprehensive literature search was conducted in the three electronic databases: PubMed, Embase, and Cochrane Library. Included studies were critically appraised using appropriate tools (risk of bias 2, ROBINS-I). A protocol was registered in the International Prospective Register of Systematic Reviews (CRD42019127131). A meta-analysis of four randomised controlled trials (RCTs) including 3931 participants showed no effect of vitamin D supplementation on CAs, a relative risk of 0.76 (95% CI 0.45; 1.30), with moderate certainty in the effect estimates by GRADE assessment. Of the nine identified observational studies, six were excluded due to a critical risk of bias in accordance with ROBINS-I. Among the included observational studies, two studies found no association, whereas one case-control study identified an association between s-25OHD < 20 nmol/L and neural tube defects, with an adjusted odds ratio of 2.34 (95% CI: 1.07; 5.07). Interpretation of the results should be cautious given the low prevalence of CAs, RCTs with onset of supplementation after organogenesis, and low-quality observational studies.
Asunto(s)
Defectos del Tubo Neural , Vitamina D , Femenino , Embarazo , Humanos , Vitaminas , Estudios de Casos y Controles , Suplementos DietéticosRESUMEN
Background: Insulinomas are very rare in childhood with sparse knowledge on the clinical aspects and the presence of Multiple Endocrine Neoplasia type 1 (MEN1). Methods: We conducted a retrospective review of patients diagnosed with insulinoma between 1995 and 2021, presenting to one referral centre in Russia. Clinical, biochemical, genetic, imaging and histological data were collected. In addition, follow-up and family data were obtained. Results: A total of twenty-two children aged 5 to 16 years were identified. The median (range) gap between the first hypoglycaemia symptoms and diagnosis was 10 (1-46) months. Twelve children (55%) were misdiagnosed to have epilepsy and were treated with anticonvulsants before hypoglycemia was revealed. Contrast enhanced MRI and/or CT were accurate to localize the lesion in 82% (n=18). Five patients (23%) had multiple pancreatic lesions. All children underwent surgical treatment. The median (range) diameter of removed tumors was 1.5 (0.3-6) cm. Histopathological studies confirmed the presence of insulinoma in all cases. Immunohistochemical studies revealed G2 differentiation grade in 10 out of 17 cases. Two patients were diagnosed with metastatic insulinoma. One of them had metastases at the time of insulinoma diagnosis, while the other was diagnosed with liver metastases eight years after the surgery. Eight children (36%) were found to carry MEN1 mutations, inherited n=5, de novo n=1, no data, n=2. Children with MEN1 had significantly higher number of pancreatic tumors compared to sporadic cases. All of them developed additional MEN1 symptoms during the following 2-13 years. In the five patients with inherited MEN1, seven family members had hitherto undiscovered MEN1 manifestations. Conclusions: In this large cohort of children with rare pediatric insulinomas, MEN1 syndrome and G2 tumors were frequent, as well as hitherto undiscovered MEN1 manifestations in family members. Our data emphasize the need of genetic testing in all children with insulinoma and their relatives, even in the absence of any other features, as well as the importance of a prolonged follow-up observation.
Asunto(s)
Hipoglucemia , Insulinoma , Neoplasia Endocrina Múltiple Tipo 1 , Neoplasias Pancreáticas , Humanos , Niño , Insulinoma/diagnóstico , Insulinoma/genética , Insulinoma/patología , Estudios Retrospectivos , Neoplasia Endocrina Múltiple Tipo 1/genética , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Derivación y ConsultaRESUMEN
CONTEXT: Congenital combined pituitary hormone deficiency (cCPHD) is the loss of ≥2 pituitary hormones caused by congenital factors. OBJECTIVE: We aimed to estimate the national incidence of cCPHD diagnosed before age 18 years and in subgroups. METHODS: Patients with cCPHD were identified in the Danish National Patient Registry and Danish hospital registries in the period 1996-2020. Hospital files were reviewed and incidences calculated using background population data. Incidence was the main outcome measure. RESULTS: We identified 128 patients with cCPHD; 88 (68.8%) were males. The median (range) age at diagnosis was 6.2 (0.01-19.0) years. The median (25th;75th percentile) number of hormone deficiencies at diagnosis was 3 (3; 4) at <1 year vs 2 (2; 2) at 1-17 years, P < .0001. Abnormal pituitary magnetic resonance imaging findings were seen in 70.3% (83/118). For those born in Denmark aged <18 years at diagnosis (n = 116/128) the estimated national incidence (95% CI) of cCPHD was 10.34 (7.79-13.72) per 100 000 births, with an annual incidence rate of 5.74 (4.33-7.62) per million. In subgroup analysis (diagnosis <1 vs 1-17 years), the incidence was highest in the 1-17 years subgroup, 7.97 (5.77-11.00) vs 1.98 (1.39-2.84) per 100 000 births, whereas the annual incidence rate was highest at <1 year, 19.8 (13.9-28.4) vs 4.69 (3.39-6.47) per million births. CONCLUSION: cCPHD had the highest incidence rate and the most hormone deficiencies in those diagnosed at <1 year. The incidence was highest in the 1-17 years age group, underscoring the need for multiple pituitary hormone investigations throughout childhood and adolescence in children with only 1 hormone deficiency.
Asunto(s)
Hipopituitarismo , Masculino , Niño , Femenino , Adolescente , Humanos , Lactante , Preescolar , Incidencia , Hipopituitarismo/diagnóstico , Hipopituitarismo/epidemiología , Hipopituitarismo/congénito , Hormonas Hipofisarias , Dinamarca/epidemiologíaRESUMEN
BACKGROUND: Synthetic glucocorticoid exposure in late pregnancy may be associated with higher blood pressure in offspring. We hypothesized that endogenous cortisol in pregnancy relates to offspring blood pressure (OBP). OBJECTIVE: To investigate associations between maternal cortisol status in third trimester pregnancy and OBP. METHODS: We included 1317 mother-child pairs from Odense Child Cohort, an observational prospective cohort. Serum (s-) cortisol and 24-hour urine (u-) cortisol and cortisone were assessed in gestational week 28. Offspring systolic blood pressure and diastolic blood pressure were measured at age 3, 18 months, and 3 and 5 years. Associations between maternal cortisol and OBP were examined by mixed effects linear models. RESULTS: All significant associations between maternal cortisol and OBP were negative. In boys in pooled analyses, 1 nmol/L increase in maternal s-cortisol was associated with average decrease in systolic blood pressure (ß=-0.003 mmHg [95% CI, -0.005 to -0.0003]) and diastolic blood pressure (ß=-0.002 mmHg [95% CI, -0.004 to -0.0004]) after adjusting for confounders. At 3 months of age, higher maternal s-cortisol was significantly associated with lower systolic blood pressure (ß=-0.01 mmHg [95% CI, -0.01 to -0.004]) and diastolic blood pressure (ß=-0.010 mmHg [95% CI, -0.012 to -0.011]) in boys after adjusting for confounders, which remained significant after adjusting for potential intermediate factors. CONCLUSIONS: We found temporal sex dimorphic negative associations between maternal s-cortisol levels and OBP, with significant findings in boys. We conclude that physiological maternal cortisol is not a risk factor for higher blood pressure in offspring up to 5 years of age.
Asunto(s)
Hipertensión , Hipotensión , Efectos Tardíos de la Exposición Prenatal , Femenino , Humanos , Masculino , Embarazo , Presión Sanguínea/fisiología , Hidrocortisona , Tercer Trimestre del Embarazo , Estudios Prospectivos , Factores de RiesgoRESUMEN
OBJECTIVES: Animal studies indicate a key role for vitamin D in brain development and function, but observational studies in humans only suggests a borderline positive association between prenatal vitamin D exposure and cognitive development in the offspring. Knowledge gaps include insights in exposure time window and differences by sex for the association. We aimed to investigate the association between blood concentrations of serum 25-hydroxyvitamin D measured at four different time points and intelligence quotient score at the age of 7 years, including analyses spilt by child sex. METHODS: In Odense child cohort, we included 1404 mother-child pairs with serum 25-hydroxyvitamin D data from early pregnancy to age 7 years. Full-scale intelligence quotient was assessed with Wechsler Intelligence Scale for Children - fifth edition. Associations were adjusted for maternal education, pre-pregnancy body mass index, gestational age, sex and head circumference. Subanalyses stratified by sex were performed. RESULTS: The median (interquartile range) serum 25-hydroxyvitamin D in cord was 45.88 (31.15-61.08) nmol/L; early pregnancy, 66.45 (51.29-78.74); late pregnancy, 79.13 (59.69-97.31); 7 years, 66.29 (53.45-80.23) nmol/L. The mean (standard deviation) full-scale intelligence quotient was 99.44 (11.98). In adjusted analyses, cord serum 25-hydroxyvitamin D < 50 nmol/L was associated with 2.2 points lower full-scale intelligence quotient compared to the reference (50-75 nmol/L) in boys, ß = -2.2; 95% confidence interval = [-4.3, -0.1], p = 0.039. The same association with full-scale intelligence quotient was found for early pregnancy serum 25-hydroxyvitamin D, ß = -2.5 [-4.6, -0.3], p = 0.025, primarily driven by an association in boys, ß = -4.0 [-7.2, -0.8], p = 0.015; and for serum 25-hydroxyvitamin D at 7 years in girls, ß = -3.0 [-6.0, -0.1], p = 0.042. CONCLUSION: In this cohort, serum 25-hydroxyvitamin D < 50 nmol/L in both early gestation and cord blood in boys and current serum 25-hydroxyvitamin D < 50 nmol/L in girls were independent risk factors for two to four points lower full-scale intelligence quotient at the age of 7 years. Vulnerability to hypovitaminosis D, especially in pregnancy, may relate to child sex.
Asunto(s)
Deficiencia de Vitamina D , Vitamina D , Niño , Masculino , Femenino , Humanos , Embarazo , Estudios de Cohortes , Deficiencia de Vitamina D/epidemiología , Índice de Masa Corporal , Calcifediol , InteligenciaRESUMEN
Early fetal stages of tooth development are vitamin D-dependent, suggesting an impact of vitamin D status in pregnancy on tooth mineralization in human populations. We examined the association between pregnancy and cord serum 25-hydroxyvitamin D (s-25(OH)D) and hypomineralization of the second primary molars (HSPM) in the 4-year-old children in the prospective, population-based Odense Child Cohort, Denmark. S-25(OH)D was measured in early pregnancy (<20 weeks, n = 753); late pregnancy (≥20 weeks, n = 841); and in umbilical cord blood (n = 1,241) using liquid chromatography-tandem mass spectrometry. HSPM was scored using modified European Academy of Paediatric Dentistry judgment criteria. The median [Q1;Q3] s-25(OH)D was 65.0 [49.4;78.0], 79.2 [60.4;95.8], and 45.1 [31.2;60.5] nmol/L in early pregnancy, late pregnancy, and cord blood, respectively. The prevalence of HSPM was 54.7%; creamy/white demarcated opacities 79.5%; yellowish/brownish demarcated opacities 14.9%; post-eruptive breakdown 5.2%; atypical restoration 0.4%. No univariate or adjusted associations with HSPM were detected for pregnancy or cord s-25(OH)D as a continuous variable or categorized into quartiles or routine clinical cut-offs, or when classifying HSPM by severity. In exploratory multiple regression analysis, HSPM was inversely associated with the length of gestation, adjusted odds ratio (aOR) 0.82 (95% C.I 0.74-0.92, p < 0.001), and directly associated with maternal education, aOR 1.57 (95% C.I 1.18-2.08, p = 0.002). In a population with relatively high s-25(OH)D concentrations and generally healthy mothers and children, pregnancy and cord blood vitamin D status was not associated with HSPM. The associations between HSPM and shorter gestational length and higher maternal education warrant further study.
Asunto(s)
Deficiencia de Vitamina D , Vitamina D , Preescolar , Estudios de Cohortes , Esmalte Dental , Femenino , Humanos , Diente Molar , Embarazo , Estudios Prospectivos , VitaminasRESUMEN
BACKGROUND: Blood pressure in childhood tracks into later life. Vitamin D status in adults is associated with blood pressure, but the impact of vitamin D status in pregnancy and childhood on blood pressure still needs investigation. OBJECTIVE: We investigated whether fetal rather than current vitamin D status is associated with blood pressure in children. METHODS: In a prospective observational study within the population-based Odense Child Cohort (OCC), we examined serum 25-hydroxyvitamin D2+3 [s-25(OH)D] in early and late pregnancy, cord blood, and at 5 y age, and the associations with systolic and diastolic blood pressure (SBP/DBP) in the 5-y-old children (n = 1,677). Multiple regression models were adjusted for maternal country of origin, parity, smoking during pregnancy, 5-y height, and weight. Two-stage mixed effect modeling was performed, integrating all s-25(OH)D data from pregnancy and cord blood. RESULTS: The median (IQR) s-25(OH)D in early pregnancy, late pregnancy, the umbilical cord, and at 5 y was 65.5 (50.7-78.5), 78.5 (60.3- 95.8), 45.4 (31.1- 60.7), and 71.9 (54.6- 86.5) nmol/L, respectively. The mean ±SD 5-y SBP/DBP was 101.0/63.8 (7.1/5.9) mmHg. In adjusted analyses, a 10 nmol/L increase of s-25(OH)D in early pregnancy associated with a 0.3/0.2 mmHg lower SBP/DBP at 5 y (P < 0.05). Optimal s-25(OH)D (>75 nmol/L) in early pregnancy was associated with lower 5-y SBP and DBP, ß (95% CI) -1.45 (-2.6, -0.3), and -0.97 (-1.9, -0.1), compared with reference s-25(OH)D (50-74.9 nmol/L). Two-stage analysis combining early pregnancy, late pregnancy, and cord s-25(OH)D data showed an inverse association with 5-y SBP and DBP for boys (P < 0.025) with significant sex-difference for DBP (Pinteraction = 0.004). No associations were found between s-25(OH)D and 5-y BP above the 90th percentile. CONCLUSION: Early pregnancy s-25(OH)D concentrations, especially >75 nmol/L, were inversely associated with 5-y blood pressure in the offspring. A novel identified protective effect of optimal vitamin D levels in early pregnancy on offspring BP is suggested.
Asunto(s)
Deficiencia de Vitamina D , Vitamina D , Adulto , Presión Sanguínea , Niño , Estudios de Cohortes , Femenino , Sangre Fetal , Humanos , Masculino , Embarazo , VitaminasRESUMEN
BACKGROUND: Maternal testosterone in pregnancy may have conditioning effects on offspring muscle strength. PURPOSE: To investigate possible associations between maternal testosterone concentrations in third trimester and offspring handgrip strength (HGS) at 5 years. METHODS: In the prospective, population-based Odense Child Cohort, total testosterone (TT) at gestational week 27-28 and 5-year HGS were measured in 1017 mother-child pairs. TT was measured by liquid chromatography-tandem mass spectrometry and free testosterone (FT) was calculated from TT and sex hormone-binding globulin (SHBG). Multivariable regression analyses were performed with HGSâ <â 10th percentile as cutoff for low HGS. RESULTS: Third-trimester FT concentration was 0.004 (0.002-0.007) nmol/L, geometric mean (meanâ -â SD; meanâ +â SD). The mean (SD) 5-year HGS was 8.7 (1.8) kg in boys and 8.1 (1.7) kg in girls (Pâ <â 0.001). Higher FT concentrations were associated with lower HGS (ßâ =â -0.186, Pâ =â 0.048), after adjustment for maternal age, parity, offspring sex, and 5-year height and weight. FTâ >â 0.004 nmol/L was associated with higher risk of 5-year HGSâ <â 10th percentile with odds ratios (95% CI) of 1.58 (1.01, 2.47; Pâ =â 0.047; nâ =â 1,017) and 1.69 (1.05, 2.74; Pâ =â 0.032) after further adjustment for children's organized sports in subgroup analysis (nâ =â 848). Lower HGS in relation to higher FT concentrations was found in all linear models but was not always statistically significant. HGS was not associated with maternal TT and SHBG levels. CONCLUSION: Third trimester FT was inversely associated with offspring muscle strength assessed by HGS at 5 years of age, which may suggest a negative effect of maternal FT on offspring muscle strength.
Asunto(s)
Fuerza de la Mano , Testosterona , Preescolar , Estudios de Cohortes , Femenino , Humanos , Masculino , Embarazo , Tercer Trimestre del Embarazo , Estudios Prospectivos , Globulina de Unión a Hormona Sexual/análisis , Testosterona/sangreRESUMEN
OBJECTIVE: The phenotype mediated by HNF4A/HNF1A mutations is variable and includes diazoxide-responsive hyperinsulinaemic hypoglycaemia (HH) and maturity-onset diabetes of the young (MODY). DESIGN: We characterised an international multicentre paediatric cohort of patients with HNF4Aor HNF1Amutations presenting with HH over a 25-year period (1995-2020). METHODS: Clinical and genetic analysis data from five centres were obtained. Diazoxide responsiveness was defined as the ability to maintain normoglycaemia without intravenous glucose. Macrosomia was defined as a birth weight ≥90th centile. SPSS v.27.1 was used for data analysis. RESULTS: A total of 34 patients (70.6% female, n = 24) with a mean age of 7.1 years (s.d. 6.4) were included. A total of 21 different heterozygous HNF4Amutations were identified in 29 patients (four novels). Four different previously described heterozygous HNF1A mutations were detected in five patients. Most (97.1%, n = 33) developed hypoglycaemia by day 2 of life. The mean birth weight was 3.8 kg (s.d. 0.8), with most infants macrosomic (n = 21, 61.8%). Diazoxide was commenced in 28 patients (82.3%); all responded. HH resolved in 20 patients (58.8%) following a median of 0.9 years (interquartile range (IQR): 0.2-6.8). Nine patients (n = 9, 26.5%) had developmental delay. Two patients developed Fanconi syndrome (p.Arg63Trp, HNF4A) and four had other renal or hepatic findings. Five (14.7%) developed MODY at a median of 11.0 years (IQR: 9.0-13.9). Of patients with inherited mutations (n = 25, 73.5%), a family history of diabetes was present in 22 (88.0%). CONCLUSIONS: We build on the knowledge of the natural history and pancreatic and extra-pancreatic phenotypes of HNF4A/HNF1Amutations and illustrate the heterogeneity of this condition.
Asunto(s)
Heterogeneidad Genética , Factor Nuclear 1-alfa del Hepatocito/genética , Factor Nuclear 4 del Hepatocito/genética , Hiperinsulinismo/genética , Hipoglucemia/genética , Mutación , Adolescente , Peso al Nacer , Niño , Preescolar , Estudios de Cohortes , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/genética , Diazóxido/uso terapéutico , Síndrome de Fanconi/genética , Femenino , Humanos , Hiperinsulinismo/tratamiento farmacológico , Hipoglucemia/tratamiento farmacológico , Lactante , Recién Nacido , Masculino , AnamnesisRESUMEN
PURPOSE: The coronavirus disease 2019 (COVID-19) pandemic has a severe impact on the general population. During the pandemic, children may develop emotional and psychological symptoms, including increased worries about health and illness, known as health anxiety symptoms (HASs). We aimed to explore HAS in 7-9-year-old children from the Danish Odense Child Cohort (OCC) during the first COVID-19 lockdown period in Denmark, and to examine associations with potential risk factors. MATERIAL AND METHODS: OCC is a cohort of children born between 2010 and 2012, which originally recruited 2874 of 6707 pregnancies (43%). Among the current OCC population of 2430 singleton children, 994 participated in this study (response rate 40%). Children and their parents filled out questionnaires about child HAS, family exposure to COVID-19 infection and parental HAS. Adjusted odds ratios (aORs) were calculated between high score child HAS (≥90th percentile) and covariates by use of logistic regression. RESULTS: Most children (n = 686, 69%) reported few worries about their health. Children reporting high score HAS also had higher levels of internalizing symptoms at age 5; aOR 2.15 (1.20;3.85), p = .010, and higher levels of maternal and paternal HAS; aOR 2.40 (1.44;3.97), p = .001, and 2.00 (1.10;3.65), p = .023, whereas no association with child sex or familial exposure to COVID-19 was detected (n = 65, 6.5%). CONCLUSIONS: High score child HAS during the first lockdown period of the COVID-19 pandemic was not associated with family exposure to COVID-19 infection, but to being a more anxious child a priori and to HAS in parents.
Asunto(s)
COVID-19 , Ansiedad/epidemiología , Ansiedad/psicología , COVID-19/epidemiología , Niño , Preescolar , Estudios de Cohortes , Control de Enfermedades Transmisibles , Dinamarca/epidemiología , Femenino , Humanos , EmbarazoRESUMEN
BACKGROUND: In neonates, rhesus D alloimmunization despite anti-D immunoglobulin prophylaxis is rare and often unexplained. Rhesus D alloimmunization can lead to hemolytic disease of the newborn with anemia and unconjugated hyperbilirubinemia. In past reports, transient congenital hyperinsulinism has been described as a rare complication of rhesus D alloimmunization. Our case report illustrates that rhesus D alloimmunization can result in a pseudosyndrome with severe congenital hyperinsulinism, anemia, and conjugated hyperbilirubinemia, despite correctly administered anti-D immunoglobulin prophylaxis. CASE PRESENTATION: We report of a 36-year-old, Caucasian gravida 1, para 1 mother with A RhD negative blood type who received routine antenatal anti-D immunoglobulin prophylaxis. Her full term newborn boy presented with severe congenital hyperinsulinism, anemia, and conjugated hyperbilirubinemia up to 295 µmol/L (ref. < 9), accounting for 64% of the total bilirubin. Syndromic congenital hyperinsulinism was suspected. Examinations showed a positive direct antiglobulin test, initially interpreted as caused by irregular antibodies; diffuse congenital hyperinsulinism by 18F-DOPA positron emission tomography/computed tomography scan; normal genetic analyses for congenital hyperinsulinism; mildly elevated liver enzymes; delayed, but present bile excretion by Tc99m-hepatobiliary iminodiacetic acid scintigraphy; and cholestasis and mild fibrosis by liver biopsy. The maternal anti-D titer was 1:16,000 day 20 postpartum. Y-chromosome material in the mother's blood could not be identified. This could, however, not exclude late intrapartum fetomaternal hemorrhage as the cause of immunization. No causative genetic findings were deetrmined by trio whole exome sequencing. The child went into clinical remission after 5.5 months. CONCLUSION: Our case demonstrates that rhesus D alloimmunization may present as a pseudosyndrome with transient congenital hyperinsulinism, anemia, and inspissated bile syndrome with conjugated hyperbilirubinaemia, despite anti-D immunoglobulin prophylaxis, possibly due to late fetomaternal hemorrhage.
Asunto(s)
Anemia Hemolítica Autoinmune , Colestasis , Hiperinsulinismo Congénito , Eritroblastosis Fetal , Isoinmunización Rh , Adulto , Hiperinsulinismo Congénito/genética , Femenino , Humanos , Hiperbilirrubinemia , Masculino , Embarazo , Isoinmunización Rh/complicacionesRESUMEN
BACKGROUND: Ketotic hypoglycemia (KH) without an identifiable underlying metabolic or hormonal disease is historically named idiopathic KH. The prevalence is unknown, but idiopathic KH is considered the most frequent cause of hypoglycemia beyond the neonatal period. KH in Down syndrome (DS) has not been reported. METHODS: We conducted a web-based survey on KH in DS through the non-profit patient organization Ketotic Hypoglycemia International. The responses were evaluated for consistency with KH by two authors. Two DS patient histories with documented KH were shared in more details. RESULTS: Survey data on 139 DS patients were obtained. After validation, 10 patients (7.2%) had reported episodes of documented hypoglycemia, ketosis, and/or symptoms compatible with KH beyond the neonatal period. Glucose concentrations ranged 1.2-2.9 mmol/L; betahydroxybutyrate was up to 5.5 mmol/L during hypoglycemia. One girl had trisomy 21 with no response to i.m. glucagon also had a heterozygous Xp22.23 deletion including GYG2, which protein, glycogenin 2, is a substrate for glycogen synthase. Treatment with extended release cornstarch was effective. CONCLUSION: This is the first demonstration of a possible high prevalence of KH in DS. Even though this finding needs to be confirmed in other research settings, identification of KH in DS could have a dramatic impact, as simple treatments with cornstarch, protein and frequent meals may prevent KH attacks and, analogous to other conditions with KH, improve growth, stamina and prevent overeating and obesity. GYG2 deletion may contribute to KH in DS, resembling glycogen storage disease type 0.
RESUMEN
Aim: Despite the enormous efforts to understand Congenital hyperinsulinism (CHI), up to 50% of the patients are genetically unexplained. We aimed to functionally characterize a novel candidate gene in CHI. Patient: A 4-month-old boy presented severe hyperinsulinemic hypoglycemia. A routine CHI genetic panel was negative. Methods: A trio-based whole-exome sequencing (WES) was performed. Gene knockout in the RIN-m cell line was established by CRISPR/Cas9. Gene expression was performed using real-time PCR. Results: Hyperinsulinemic hypoglycemia with diffuse beta-cell involvement was demonstrated in the patient, who was diazoxide-responsive. By WES, compound heterozygous variants were identified in the adenylyl cyclase 7, ADCY7 gene p.(Asp439Glu) and p.(Gly1045Arg). ADCY7 is calcium-sensitive, expressed in beta-cells and converts ATP to cAMP. The variants located in the cytoplasmic domains C1 and C2 in a highly conserved and functional amino acid region. RIN-m(-/-Adcy7) cells showed a significant increase in insulin secretion reaching 54% at low, and 49% at high glucose concentrations, compared to wild-type. In genetic expression analysis Adcy7 loss of function led to a 34.1-fold to 362.8-fold increase in mRNA levels of the insulin regulator genes Ins1 and Ins2 (p ≤ 0.0002), as well as increased glucose uptake and sensing indicated by higher mRNA levels of Scl2a2 and Gck via upregulation of Pdx1, and Foxa2 leading to the activation of the glucose stimulated-insulin secretion (GSIS) pathway. Conclusion: This study identified a novel candidate gene, ADCY7, to cause CHI via activation of the GSIS pathway.
Asunto(s)
Adenilil Ciclasas/genética , Hiperinsulinismo Congénito/enzimología , Hiperinsulinismo Congénito/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Adenilil Ciclasas/deficiencia , Secuencia de Aminoácidos , Animales , Sistemas CRISPR-Cas , Línea Celular , Preescolar , Hiperinsulinismo Congénito/genética , Técnicas de Inactivación de Genes , Glucosa/metabolismo , Factor Nuclear 3-beta del Hepatocito/genética , Factor Nuclear 3-beta del Hepatocito/metabolismo , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Insulina/genética , Secreción de Insulina , Masculino , Ratas , Alineación de Secuencia , Transactivadores/genética , Transactivadores/metabolismoRESUMEN
Idiopathic ketotic hypoglycemia (IKH) is a diagnosis of exclusion with glycogen storage diseases (GSDs) as a differential diagnosis. GSD IXa presents with ketotic hypoglycemia (KH), hepatomegaly, and growth retardation due to PHKA2 variants. In our multicenter study, 12 children from eight families were diagnosed or suspected of IKH. Whole-exome sequencing or targeted next-generation sequencing panels were performed. We identified two known and three novel (likely) pathogenic PHKA2 variants, such as p.(Pro869Arg), p.(Pro498Leu), p.(Arg2Gly), p.(Arg860Trp), and p.(Val135Leu), respectively. Erythrocyte phosphorylase kinase activity in three patients with the novel variants p.(Arg2Gly) and p.(Arg860Trp) were 15%-20% of mean normal. One patient had short stature and intermittent mildly elevated aspartate aminotransferase, but no hepatomegaly. Family testing identified two asymptomatic children and 18 adult family members with one of the PHKA2 variants, of which 10 had KH symptoms in childhood and 8 had mild symptoms in adulthood. Our study expands the classical GSD IXa phenotype of PHKA2 missense variants to a continuum from seemingly asymptomatic carriers, over KH-only with phosphorylase B kinase deficiency, to more or less complete classical GSD IXa. In contrast to typical IKH, which is confined to young children, KH may persist into adulthood in the KH-only phenotype of PHKA2.